Statins, of which the representative examples may be selected from rosuvastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, bervastatin, dalvastatin or their analogs or pravastatin, simvastatin, lovastatin or their analogs share a characteristic structure, consisting of respectively a heptenoic or heptanoic acid moiety (free acid, salt or lactone) connected to the aromatic or alicyclic core. Biological activity of statins is closely related to their stereochemistry, especially configuration at the chiral atoms of said heptenoic or heptanoic acid moiety.
Document U.S. Pat. No. 5,527,916 describes a process for the separation of at least one isomer from a mixture of isomers of a tetrahydropyran-2-one having at least two chiral centers.
WO 2005/092867 A2 discloses the use of different lactone derivatives in the preparation of statins, particularly rosuvastatin.
Sequential aldol reactions catalyzed by deoxyribose aldolase are described in J. Am. Chem. Soc. 117, 29, (1995) p. 7585.
An asymmetric aldol reaction with three differently substituted acetaldehyde substrates catalyzed by 2-deoxy-ribose-5-phosphate aldolase (DERA) shows that not all acetaldehyde derivatives are equally accepted as substrates for DERA (J. Am. Chem. Soc. 116 (1994), p. 8422-8423). The reaction time of the enzymatic catalysis was 6 days. The resulting lactone was oxidized with Br2 and BaCO3.
In WO 2006/134482 A1, a 2-deoxyribose-5-phosphate aldolase (DERA) catalyzed aldol addition step is included in a process for forming atorvastatin. The aldolase belongs to the class EC 4.1.2.4.
WO 05/118794 deals with an improvement of the DERA enzyme. The isolated mutant enzymes may be used for the preparation of a 2,4-dideoxyhexose or a 2,4,6-trideoxyhexose having a high variety of substituents.
The object of the present invention is to provide valuable intermediate compounds and processes as building blocks for effectively producing statins.
A further object of the invention is to produce intermediate compounds with inexpensive starting materials and simple equipment.